Alzheimer's disease BIN1 coding variants increase intracellular Aβ levels by interfering with BACE1 recycling

Abstract

Genetic studies have identified BIN1 as the second most important risk locus associated with late-onset Alzheimer's disease (LOAD). However, it is unclear how mutation of this locus mechanistically promotes Alzheimer’s disease (AD) pathology. Here we show the consequences of two coding variants in BIN1 (rs754834233 and rs138047593), both in terms of intracellular beta-amyloid (iAbeta) accumulation and early endosome enlargement, two interrelated early cytopathological AD phenotypes, supporting their association with LOAD risk. We previously found that Bin1 deficiency potentiates iAbeta production by enabling BACE1 cleavage of the amyloid precursor protein in enlarged early endosomes due to decreased BACE1 recycling. Here, we discovered that the expression of the two LOAD mutant forms of Bin1 does not rescue the iAbeta accumulation and early endosome enlargement induced by Bin1 knockdown and recovered by wild-type Bin1. Moreover, the overexpression of Bin1 mutants, but not wild-type Bin1, increased the iAbeta42 fragment by reducing the recycling of BACE1, which accumulated in early endosomes, recapitulating the phenotype of Bin1 knockdown. We showed that the mutations in Bin1 reduced its interaction with BACE1. The endocytic recycling of transferrin was similarly affected, indicating that Bin1 is a general regulator of endocytic recycling. These data demonstrate that the LOAD-coding variants in Bin1 lead to a loss of function in endocytic recycling, which may be an early causal mechanism of LOAD.

Endosomal trafficking and related genetic underpinnings as a hub in Alzheimer's disease

“…Moreover, it has been also shown that BIN1 depletion impacts BACE1 trafficking, causing its endosomal accumulation and, consequently, favoring Aβ production (Ubelmann et al, 2017 ). In line with this evidence, rare coding variants including rs754834233 or rs138047593 impact on AD risk reducing BACE1 recycling and causing early endosome enlargement recapitulating the same phenotype of Bin1 knockdown (Perdigão et al, 2021 ; Vardarajan, Ghani, et al, 2015 ). Beside this, BIN1 expression correlates also with tau pathology (Calafate et al, 2016 ), indeed it directly interacts with tau and such interaction is downregulated by tau phosphorylation on Thr231 (Sottejeau et al, 2015 ).…”

BIN1K358R suppresses glial response to plaques in mouse model of Alzheimer's disease

“…58,59 Notably, the presence of the K358R vari- explored, but a previous report found that K358R mutation resulted in increased accumulation of Aβ42 in vitro. 4,32 While we observe an appropriate microglial response to these plaques in terms of plaque-associated microglia, we find that the astrocytic response is profoundly blunted. We observe this through impairments in plaque-associated GFAP + astrocytes in the cortex, both in terms of number and cell size.…”

“…recycling by a larger extent (70%) compared to the P318L mutation (30%). 32 To investigate the effect of the BIN1K358R variant in vivo, we introduced the variant into the mouse Bin1 gene and interbred BIN1 K358R mice with the 5xFAD mouse model of amyloidosis, to explore its impacts on both normal brain function, as well as its interaction with aggressive amyloidosis (ie, induced by the 5xFAD transgene array). The K358R variant is located in the SH3 domain of BIN1, where it binds to proline-rich domains of proteins like Tau, clathrin, and clusterin.…”

“…These GO hits align with the main functions of Bin1, which include clathrin-mediated endocytosis, intracellular endosome and vesicle trafficking, cytoskeleton remodeling, and membrane lipid binding to induce membrane curvature. 6,20,32,43 Notably, several of the DEGs in our dataset have been described as marker genes for diseaseassociated astrocytes (DAAs 44 ) and DAOs 45 (Figure 4F). All DAA and DAO genes differentially expressed in our dataset were significantly downregulated in 5xFAD/BIN1 K358R versus 5xFAD mice, including Gfap, Vim, Aqp4, Clu, Serpina3n, Fxyd1, C4b, and Cd9.…”

Phosphatidylinositol (3,5)-bisphosphate machinery regulates neurite thickness through neuron-specific endosomal protein NSG1/NEEP21

“…Neurons are highly susceptible to disruption in the endosome/lysosome system ( 67 , 68 ). Genetic variants of endosomal proteins such as BIN1 ( 69 ), SORL1 ( 70 ), CD2AP ( 71 ) have been implicated in Alzheimer’s disease. Similarly, mutations in Vps35 ( 72 ), LRRK2 ( 73 ), and RME8 ( 74 ) are associated with Parkinson’s disease.…”